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Environmental classification of pharmaceuticals in www.fass.se – guidance for pharmaceutical companies, June 2012

Introduction

The Swedish environmental classification of pharmaceuticals at www.fass.se has now been running since October 2005. Since then a large amount of environmental information of pharmaceuticals has been published.

One of the main reasons for the introduction of environmental information at www.fass.se was the growing public interest in the possible environmental effects of pharmaceuticals. The public interest led to political interest and therefore a significant pressure from the Swedish government for more knowledge about the possible environmental impact of pharmaceuticals.

In 2002, the government instructed the Swedish Medical Products Agency (MPA) to conduct a survey of the state of knowledge on the environmental effects of pharmaceuticals, cosmetics and hygiene products. In its final report, from 2004, the Swedish MPA concluded that EU rules applied and that it was not legally possible to implement a mandatory environmental classification and labelling system in Sweden. Nevertheless, the former Minister of the Environment, Lena Sommestad, made it clear that she expected better information on environmental effects of pharmaceuticals.

Thus LIF, the association for the research based pharmaceutical Industry in Sweden, took the initiative to develop a voluntary environmental classification scheme, in partnership with other interested parties in the healthcare sector. The model was developed in 2004-2005 by LIF, Stockholm County Council, the pharmacy monopoly chain Apoteket AB (today the Swedish Pharmacy Association represents the pharmacies), the Swedish Association of Local Authorities and Regions and the MPA. The goal was to develop a transparent model for the public, the healthcare sector and researchers.

The environmental information, focusing on the aquatic environment, is based on data from the pharmaceutical companies but is reviewed by an independent organization, the Swedish Environmental Research Institute (IVL).

This is the second time the guideline is updated since the start in 2005. The last edition was published in 2007. It is intended that the classification scheme will be reviewed on an on-going basis. Thus, it may be subject to future refinement, based on developing scientific principles, new data and regulatory guidance.

1. Presentation of Environmental Information at www.fass.se

The environmental information is presented at www.fass.se and is available for the Active Pharmaceutical Ingredients (APIs) for each product in the environmental tab called “Miljö” (Figure 1). www.fass.se is the Swedish medicines information portal open to the public.

The first level of information contains summary phrases about the environmental risk, degradation and bioaccumulation. The next level is detailed background information directed to people specifically interested in the environmental data and the underlying basis of the risk assessment.

Please note that the summary phrases will be given in Swedish at www.fass.se, although English translations are available in this document for comparison. However, the detailed background information can be given in English.

The first level of information provides summary phrases based on simple aquatic environmental risk, degradation and bioaccumulation. The environmental risk phrase (Table 1) is based on the PEC/PNEC ratio (Predicted Environmental Concentration / Predicted No Effect Concentration) of the API. The PEC/PNEC ratio decides the wording of the aquatic environmental risk phrase (to be given in Swedish at www.fass.se).

Table 1. Summary phrases for the environmental risk.

Environmental risk

PEC/PNEC ratio

Summary phrase, English

Summary phrase, Swedish

PEC/PNEC ≤ 0.1

Use of *name of the substance* has been considered to result in insignificant environmental risk.

When PEC/PNEC <1 but the substance is flagged as a potential PBT (Persistent, Bioaccumulative and Toxic) or vPvB (very Persistent and very Bioaccumulative).

Hazardous environmental properties.

Särskilt miljöfarliga egenskaper.

For some APIs, data may be lacking due to limited use/low dose which, in turn, means the action limit in the EU EMA Environmental Risk Assessment guideline (EMA/CHMP/SWP/4447/00) of PEC < 0.01 µg/L is not triggered and, consequently, an environmental risk assessment may not have been undertaken. In these cases the following phrase should be included in the detailed background information (to be given in English or Swedish):

In English: According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of * name of the substance* is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) is below the action limit 0.01 µg/L.

According to the EU EMA guideline for Environmental Risk Assessment of pharmaceuticals (Ref. 1), vitamins, electrolytes, amino acids, peptides, proteins, carbohydrates and lipids are exempted because they are unlikely to result in significant risk to the environment. Similarly vaccines and herbal medicinal products are also exempted due to the nature of their constituents.

There might also be other pharmaceuticals on the Swedish market that could be exempted due to the nature of their constituents e.g. activated carbon. In these cases the companies should supply the reviewer with enough information to justify the exemption. Substances that, due to their volatility or other physical parameters, cannot be assessed for aquatic environmental fate and effects are also exempted. The justification of the exemption should be included in the detailed background information.

No environmental information will normally be provided for the exempted pharmaceuticals, and the following summary phrases (Table 4) will be used in the first level of information.

Table 4. Summary phrases for exempted substances

Exempted substances

Substance

Summary phrase, English

Summary phrase, Swedish

Vitamins

Use of vitamins has been considered to result in insignificant environmental impact.

Användning av vitaminer bedöms inte medföra någon miljöpåverkan.

Electrolytes

Use of electrolytes has been considered to result in insignificant environmental impact.

Användning av elektrolyter bedöms inte medföra någon miljöpåverkan.

Amino acids, proteins and peptides

Use of amino acids/peptides/proteins has been considered to result in insignificant environmental impact.

The reviewer may request additional information from companies to justify the exemption and ensure consistency in the approaches used. The justification for an exempted substance should also be given in the detailed background information. If the exemption refers to the EMA guideline (Ref. 1) the detailed background information should also include the following reference phrase (to be given in English or Swedish):

In English: According to the European Medicines Agency guideline on environmental risk assessments for pharmaceuticals (EMA/CHMP/SWP/4447/00), vitamins, electrolytes, amino acids, peptides, proteins, carbohydrates, lipids, vaccines and herbal medicinal products are exempted because they are unlikely to result in significant risk to the environment.

Depending on the characteristics of the substance, the reviewer may request full environmental information from companies even though the substance is exempted according to the EMA guideline (Ref. 1), e.g. peptides used as antibiotics.

1.2 Detailed background information

Detailed environmental information and the underlying basis of the risk assessment can be found under the link “Läs Mer” (‘Read More’). Please see section 2.1 Data Collection for guidance on which information to include, and Appendix 1 for an example of how to present data.

Please note that in some cases the detailed background information should include a justification of an exempted substance (see 1.1.1) or a clarification of why environmental data is lacking (see 1.1).

1.3 Data sharing

A mechanism for data sharing, review and publication within the Fass database is available e.g. for generic compounds (i.e. if a company has taken the lead responsibility for compiling the environmental data and undertaking the classification).

Companies lacking environmental data for the APIs will be able to link to the environmental information produced by another company. In that case the following text will automatically appear below the headline "Environmental impact/Miljöpåverkan" (Table 5):

Table 5. Information presented in case of data sharing.

English phrase for data sharing

Swedish phrase for data sharing

Environmental information for *name of the substance* originates from *name of the company* for *product name*.

1.4 References

References, internal (e.g. company technical reports) or external (publicly available reports and publications), should be given in association with all the submitted data and in a reference list in the end of the detailed background information. On request by the reviewer, additional information should be provided to clarify the data. Confidentiality will be maintained where appropriate.

2. How to assess environmental risk, degradation and bioaccumulation

2.1 Data Collection

It is advisable that the main excreted active form is assessed. If these data are not available, data for the parent compound should be used. For combination products, each active ingredient should be assessed.

It is preferred to use experimental data rather than estimated data (e.g. measured ecotoxicity/Dow vs QSAR). If estimated data are used, the company should justify the scientific rationale.

Environmental information on pharmaceutical compounds published in scientific peer reviewed journals has become more available during the last few years. To make sure all relevant data are considered, companies should take into account relevant published data when evaluating the environmental risk and hazard of the API. The environmental test results, together with the test guidelines followed (OECD, FDA etc.), should be presented. If the test is not standardized, see 2.2.4, 2.3.4, 2.4.1 and Appendix 2 for further guidance.

In some cases the reviewer may request additional information from companies to ensure consistency in the approaches used.

2.1.1 The following information, where available, should be used when classifying the APIs

Sales data in kilograms of API in Sweden (including all products and enantiomers containing the same API and all salts of the API (e.g. metoprolol succinate and metoprolol tartrate) should be taken into account). For marketed products, data from the most recent year will be provided by LIF in Sweden through cooperation with IMS Health. For newly introduced products (on patent), it is recommended to use the forecasted sales five years after launch when calculating the environmental risk. If forecasted sales data are considered to be confidential, it is allowed to calculate a theoretical interval of quantity substance, based on the environmental risk class to be used, and thereafter state that the forecasted sales in kg are between the limits of this interval.

Excretion of parent compound after use, as % of given dose.

Excretion of metabolites after use, as % of given dose, including:

Identification of the metabolites, including specification of conjugates, which may deconjugate to the parent compound in a sewage treatment plant.

Pharmacological activity (or ecotoxicity, if known) of the metabolites compared with the parent compound.

Short-term and long-term effects data for algae, crustaceans (usually Daphnia magna or Ceriodaphnia dubia) and fish. Please provide the species names both in Swedish (or English) and in Latin.

Risk assessment, i.e. PEC/PNEC, calculations as well as the specific PEC and PNEC calculation, given in μg/L, where applicable

Monitoring data showing sewage treatment plant (STP) removal and/or concentrations in the environment. If any of these data are used, the company should justify the scientific rationale. In some cases the reviewer may request additional information from companies to ensure consistency in the approaches used.

The bioconcentration factor (BCF), and/or partition coefficient log Kow (often referred to as log Pow or log P). Log Dow or log Dlipw can also be used if appropriate.

All data should, where possible, be supported by the appropriate OECD, FDA or similar guidelines. Table 6 shows some comparable test guidelines.

Table 6. Some comparable OECD and FDA test guidelines.

Test

OECD guideline

FDA guideline

Algal growth inhibition

201

4.01

D. magna, acute toxicity

202

4.08

D. magna, chronic toxicity

211

4.09

Fish, acute toxicity

203

4.11

Hydrolysis

111

3.09

Soil sorption/desorption

106

3.08

Ready biodegradability

301

3.11

Inherent biodegradability

302

3.12

2.2 Environmental Risk Assessment (ERA)

In order to assess the environmental risk of an API, the Predicted Environmental Concentration (PEC) and the Predicted No Effect Concentration (PNEC) need to be calculated.

2.2.1 Predicted Environmental Concentration (PEC)

The PEC is obtained by using the following formula, and is based on the total sales of API in kg/year in Sweden:

PEC (μg/L) = (A*109*(100-R))/(365*P*V*D*100) = 1.5*10-6*A(100-R)

where:

A (kg/year) = total actual API sales (active moiety) in Sweden for the most recent year (will be obtained from LIF).

R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available.

The factor of 1000000000 in the equation converts the quantity used from Kg to μg.

The factor of 365 in the denominator converts from annual to daily quantity used. Simplifying all the default values into a single factor gives the second equation.

2.2.1.1 Metabolism

The PEC calculation can consider the extent of metabolism of the active moiety to less pharmacologically active or inactive compounds, e.g. kg x 10% x 0.5 for a metabolite found at a level of 10% and that has half the pharmacological activity of the main active ingredient. This is effectively the same as the FDA approach (Ref. 4). Note, if humanmetabolism and pharmacological activity of the metabolites are used to refine the PEC calculation, then sufficient data should be provided to support the assumptions made. Specifically, both the amount of metabolite present (as a fraction of excreted material) and the relative pharmacological activity compared to the main active moiety should be provided. It should not be assumed that human metabolites are inactive without supporting information.

If there is uncertainty about the relative potency of metabolites, or the amounts excreted, it is recommended to assume that 100% is excreted as the active parent molecule. This is considered to represent a reasonable worst case.

2.2.1.2 STP removal

STP simulation studies (e.g. OECD 303) can be used directly for predicting removal during sewage treatment. If Ready or Inherent biodegradability test results are available (OECD 301 and 302 series), the SimpleTreat model may be used to calculate removal during sewage treatment (see ECHA Ref. 3, Appendix R.16-3). It is recommended to use SimpleTreat, but alternative models may be used if reasonably justified.

If an OECD 308 study is available and demonstrates >60% mineralization (or 90% primary degradation) by the end of the 100d test period, it is considered reasonable to assume that the substance would be readily removed in a sewage treatment plant. When using SimpleTreat to calculate the removal rate when these criteria are met, the substance may be regarded as “readily biodegradable but failing the 10d window”.

2.2.1.3 Measured Environmental Concentration (MEC)

In principle it should be possible to use measured concentrations (MEC) instead of predicted environmental concentrations, if such data are sufficient to ensure a representative exposure assessment. Adequate supporting information should be provided to justify the interpretation of the results. In some cases the reviewer may request additional information from companies to ensure consistency in the approaches used. In the detailed background information, however, it is still expected to find both the MEC and PEC figures to enable comparison.

2.2.2 Predicted No Effect Concentration (PNEC)

Ideally, ecotoxicological data should be provided for three trophic levels (usually algae, crustaceans (D. magna or C. dubia) and fish). However, if relevant data are available for the species believed to be most sensitive, based on an understanding of receptor-mediated effects for example, then it may still be possible to derive a PNEC with data from only one or two species.

If a valid PNEC cannot be calculated, the phrases; ‘Risk of environmental impact of *name of the substance* cannot be excluded, since no ecotoxicity data are available’ or ‘Risk of environmental impact of *name of the substance* cannot be excluded, since there is not sufficient ecotoxicity data available’ should be used.

2.2.2.1 Assessment Factors

The PNEC should preferably be obtained by applying assessment factors (AF) to long-term ecotoxicity data in accordance with the ECHA guidance (Ref. 3, Table R.10-4). If long-term data is lacking, short-term ecotoxicity data may be used. An AF of 1000 is normally applied to the most sensitive of three short-term toxicity (LC/EC50) endpoints. However, the AF may be reduced to 100, 50 or 10, depending on the number of long-term NOEC endpoints available, providing long-term data are available for the species with the lowest acute LC/EC50.

The AF recommended in the ECHA guidance may not always be applicable, e.g. if particularly sensitive species are identified, based on evaluation of the mode of action of the API, or if mammalian toxicology or data from similar compounds indicate that a higher or a lower AF would be more appropriate. This needs to be considered on a case-by-case basis, with justification provided for the AF used. For instance, cyanobacteria (Cyanophyta) are recommended for effects testing of antimicrobials (see EMA guideline, p. 6 (Ref. 1) and EMA Q&A Question 11.1 (Ref. 2)). To calculate the PNEC from an anti-microbial effect study with cyanobacteria, a default AF of 10 is applied to the NOEC (see EMA guideline, p. 7 (Ref. 1)).

2.2.3 PEC/PNEC ratio

The environmental risk is estimated by calculating the PEC/PNEC ratio. This defines the appropriate risk phrase to be used in the classification scheme. Please see section 1.1.

2.2.4 Use of non-standard data in the ERA

If the test is not standardized, this should be noted, and the company should provide enough information to facilitate interpretation of the results by an independent reviewer and other interested parties. This includes type of endpoint and its ecological relevance, but also other relevant information such as medium, temperature, exposure regime, number of replicates and test geometry (see Appendix 2 for further information).

2.3 Assessment of degradation

This section is intended to assess the degradation potential of the APIs. Note that the phrases do not necessarily relate to the ’P’ criteria in PBT/vPvB assessment according to REACH.

Persistence is characterized by the potential for a substance to remain undegraded or unchanged in the environment. Degradation mechanisms can be biotic (biodegradation) and/or abiotic.

In practice, biodegradation in the environment is normally extrapolated from laboratory experiments such as Ready tests (e.g. OECD 301 series), Inherent tests (OECD 302 series) or simulation studies (OECD 303/307/308/309). Mineralisation reduces a pharmaceutical to its basic constituents, which are considered to present no significant environmental risk. Primary degradation of a molecule might also significantly reduce or eliminate its pharmacological activity. In such cases, information should be provided to demonstrate the expected reduction in ecotoxicity. This might be based on direct measurement or, if the identity of the transformation product is known and a suitable analytical standard exists, on a comparison with human metabolites and their relative pharmacological activity, for example.

2.3.1 Interpretation of biodegradation studies (ready and inherent)

If a substance passes the criteria for ‘ready’ biodegradability, as defined in the OECD 301 test guideline series (or equivalent), the phrase ‘The medicine is degraded in the environment’ should be used. If a substance does not pass the criteria for ready biodegradability but the test shows significant mineralisation, the phrase ‘The medicine is slowly degraded in the environment’ should be used.

If a substance passes the criteria for ‘inherent’ biodegradability, as defined in the ECHA Guidance (see below (Ref ECHA Table R. 11-2)), the phrase ‘The medicine is slowly degraded in the environment’ should be used:

If a substance fails to meet the above criteria, and there are no simulation studies or analytical monitoring data to support elimination within the ECHA persistence half-lives, the phrase ‘The medicine is potentially persistent’ should be used.

2.3.2 Interpretation of simulation study OECD 308

Fundamentally, the data generated from an OECD 308 study does not lend itself to the generation of independent half-lives for water and sediment since the test system represents a dynamic interaction between the two compartments. Furthermore, the presence of bound (unextractable) sediment residues often makes determination of half-lives in sediment impossible in practice. Consequently, the concept of a ‘total system’ half-life has been introduced to support this classification scheme.

The following guidance on the interpretation of OECD 308 data represents a practical approach. OECD guidelines do not provide any definitive fail/pass criteria for the OECD 308 study and there is only limited regulatory precedent for the values used in this scheme. This approach will be reviewed on an on-going basis and may be subject to future refinement based on developing scientific principles, new data and regulatory guidance. The criteria for OECD 308 results for the different degradation phrases are shown in Table 7.

Table 7. Summary of pass criteria for degradation phrases based on OECD 308.

Pass criteria

Summary phrase

DT50 ≤ 32d for the total system.

The substance is degraded in the environment.

DT50 ≤ 120d for the total system.

The substance is slowly degraded in the environment.

DT50 >120d for the total system.

The substance is potentially persistent.

When assigning a classification based on OECD 308 data, the following points should also be noted:

For purposes of this guidance document, DT50 is calculated as the time in days it takes for the amount of total parent material that can be extracted from the whole water/sediment system to reach 50 percent of the initial amount of parent material used to dose the test system. DT50 collectively represents the loss of parent from the test system due to its biological or chemical transformation, mineralization and/or irreversible binding to sediments.

For classification purposes, DT50 values should represent the disappearance rate of the parent molecule.

The total system DT50 should be calculated from the total amount of parent compound (i.e. water and sediment extractions added together) compared to the total amount applied at the start of the study. In practice, this normally means comparing the amount of radioactivity present as parent compound compared to the total amount of radioactivity applied at the start of the study.

The phrase ‘The substance is degraded in the environment’ should not be used if there is >15% remaining as parent compound at the end of the study, regardless of the DT50 values obtained. If the DT50 values fulfil the criteria for the phrase ‘The substance is degraded in the environment’ but there is in total >15% parent compound remaining at the end of the study (water + sediment extract) then the phrase ‘The substance is slowly degraded in the environment’ should be used.

As long as all reasonable efforts have been made to extract sediment residues (e.g. by using a range of extraction conditions), any remaining bound residue can be considered as not bioavailable and removed from the system for the purposes of calculating DT50’s. Companies should provide information on the extraction methods used in order to justify this approach.

Normally data for two sediments are available. If, according to the above DT50 criteria, different degradation phrases would be obtained from each sediment, then the phrase ‘The substance is slowly degraded in the environment’ should be used. This may occur if the compound is ‘degraded’ in one sediment and ‘slowly degraded’ in the other, or if the compound is ‘degraded’ or ‘slowly degraded’ in one sediment, but ‘potentially persistent’ in the other.

The cut-off value DT50 ≤ 32d for disappearance of parent extracted from the total system is based on a combination of:

The following text from ECHA guidance: ”Rapid degradation in the aquatic environment may be demonstrated by other data than referred to using the standard assessment methods covered above. This may be data on biotic and/or abiotic degradation. Data on primary degradation can only be used where it is demonstrated that the degradation products shall not be classified as hazardous to the aquatic environment, i.e. that they do not fulfil the classification criteria. Scientific evidence must be provided that the substance is degraded in the aquatic environment to a level of >70% within a 28-day period. If first-order kinetics is assumed, which is reasonable at the low substance concentrations prevailing in most aquatic environments, the degradation rate will be relatively constant for the 28-day period. Thus, the degradation requirement will be fulfilled with an average degradation rate constant, k > 0.043 day-1 which corresponds to a degradation half-life of 16 days.”

The ratio of 3 for the P criteria for water and sediment (Table 9), and;

Taking the mean of the water and sediment half-life to produce a total system half-life.

Thus, in the same way that is 3 x 40d =120d (Table 9), 3 x 16d = 48d. The total system half-life of 32d is then simply the average of 16d and 48d.

The cut-off DT50 value of 120d for disappearance of parent extracted from the total system is consistent with the typical duration of an OECD 308 study.

2.3.3 Interpretation of abiotic degradation studies

Abiotic degradation is normally determined from hydrolysis studies (OECD 111) or photodegradation studies (e.g. OECD 316). In principle, these can be used to demonstrate lack of persistence if the predicted half-life in the environment is less than the half-life required to fulfil the ‘P’ criteria (Table 9). However, as discussed above, these are primary degradation mechanisms and hence information on the identity of major transformation products, and their expected ecotoxicity, should also be provided. If these conditions are met the phrase ‘The substance is slowly degraded in the environment’ should be used. If photolysis data are used, consideration should be given to the extrapolation from laboratory to Swedish environmental conditions. For substances that undergo rapid hydrolysis (half-life <40 days at environmentally relevant pH and temperatures) there should be no further biodegradation testing requirements based on the parent compound. Additional fate and effects data should be provided on the hydrolysis products where available.

For substances potentially fulfilling the EU PBT/ vPvB criteria, further information on persistence will be required which may involve a more detailed assessment of the potential ecotoxicity of any significant primary degradation products.

Ultimately, it is the half-life in the environment that is required in order to characterize the persistence of a compound. Hence a ‘weight-of-evidence’ approach is invariably needed in order to ensure appropriate interpretation of measured and predicted degradation data, particularly where conflicting data exist. In all cases, sufficient supporting evidence should be provided in the detailed background information in order to justify the classification given.

2.3.4 Use of non-standard data when assessing degradation

To ensure consistency within the classification scheme, use of non-standard studies for characterizing persistence should be supported by sufficient information to allow adequate interpretation of the results. Such information could include source and concentration of inoculum; information on pre-exposure, temperature, test substance concentration, DO, pH, analyte (e.g. parent compound or CO2), number of time points, number of replicates & test geometry.

2.4 Assessment of Bioaccumulation

The most widely accepted measure of bioaccumulation potential is the Bioconcentration Factor (BCF). In order to classify the APIs based on their potential to bioaccumulate, the EU Classification, Labelling and Packaging (CLP) guideline (Ref. 5) is used. According to CLP, a BCF in fish of ≥ 500 is indicative of the potential to bioconcentrate, for classification purposes. In the context of PBT/vPvB assessment in the ECHA guidance, the B and vB triggers are BCF=2000 and 5000 respectively (Ref. 3, Table R. 11-1). Note that the phrases do not necessarily relate to the ’B’ criteria in PBT/vPvB assessment according to ECHA.

In the absence of a measured BCF value, the bioaccumulation potential may be indicated from log Kow (often referred to as log Pow or log P), which describes partitioning of the neutral form of the molecule. The CLP guideline states that a log Kow > 4 indicates that the substance may bioaccumulate. For complex ionic molecules it is more relevant to use log Dow at pH 7 (see below) (Ref. 3, R.7a, p. 106), but the principle is the same. Note that whilst log Dow ≥4 indicates a potential to bioaccumulate in aquatic organisms, this does not fulfil the ’B’ criteria in PBT/vPvB assessment, which would normally be based on a BCF derived from a bioaccumulation study.

Hence, one of the following phrases should be included (Table 8):

Table 8. Bioaccumulation phrases based on test results.

BCF or partition coefficient result

English phrase

Swedish phrase

BCF < 500 or log Dow (at pH 7) < 4

*Name of the substance* has low potential for bioaccumulation.

*Substansnamnet* har låg potential att bioackumuleras.

BCF ≥ 500 or log Dow (at pH 7) ≥ 4

*Name of the substance* has high potential for bioaccumulation.

*Substansnamnet* har hög potential att bioackumuleras.

The Kow is defined as the partition coefficient of the neutral form of a substance. The Dow is the octanol/water distribution coefficient of all the forms (neutral and ionisable) of a substance and is the actual experimental result. For neutral molecules, Dow will approximate to Kow, but for ionisable molecules Kow is derived by correcting by the acid dissociation constant pKa using the relationship Kow=Dow(1+10(abs(pH-pKa))) (Equation 1). However, log Kow and log Dow may both be poor predictors of bioaccumulation for large complex ionisable compounds, as the partitioning mechanism may be more complex than simple partitioning of the neutral species. Hence, use of log Dow (at pH 7) is preferred for ionisable compounds, consistent with ECHA guidance (Ref. 6, R. 7a), as it may better represent the actual partitioning behaviour, i.e. if log Dow ≥4 at pH 7 then the summary phrase will be ‘The substance has high potential for bioaccumulation’. Care should be taken when using computer-estimated log Kow (ClogP) values, as many of these are based solely on the neutral molecule. If only such values are available, estimated log Dow can be generated from estimated log Kow using Equation 1 above.

Where available, measured liposome/water distribution coefficients (log Dlipw) at pH ~7 can be used as a further substitute for bioaccumulation (Ref. 6).

Overall, it should be noted that the use of log Kow relationships, or even log Dow, for estimating BCFs for ionisable compounds is questionable. For example, Meylan et al. (Ref. 7) evaluated a large data set of both non-ionic and ionic compounds. Whilst reasonable regression equations were obtained for non-ionic compounds, no acceptable regression was obtained for ionic compounds. These data suggest that significant bioaccumulation potential is unlikely for ionisable compounds. However, the fact that no clear correlations were observed suggests that log Kow may be a poor predictor of bioaccumulation potential.

In summary, for the purpose of this classification scheme, the BCF should be used to select the appropriate phrase. If no measured BCF is available, log Kow, log Dow or log Dlipw at pH 7 can be used. However, further discussion concerning the relevance of the available data, possibly referencing the work by Meylan et al. (Ref. 7), may be included in the detailed background information.

2.4.1 Use of non-standard data when assessing bioaccumulation

To ensure consistency within the classification scheme, use of non-standard studies for characterizing bioaccumulation should be supported by sufficient information to allow adequate interpretation of the results.

2.5 PBT/vPvB Assessment criteria

The REACH criteria for PBT/vPvB Classification are given in Table 9. For the purpose of this classification scheme, and where relevant data are available, any compound meeting the criteria given in Table 9 will be flagged as a PBT or vPvB, as appropriate. Note that all three properties, ie ‘P’, ‘B’ and ‘T’ are required in order to classify a compound as ‘PBT’

Table 9. PBT and vPvB criteria according to ECHA

PBT criteria

vPvB criteria

P

Half-life >60 d in marine water or >40 d in freshwater* or half-life >180 d in marine sediment or >120 d in freshwater sediment*.

Half-life >60 d in marine water or freshwater or half-life >180 d in marine or freshwater sediment.

B

BCF >2000

BCF > 5000

T

Chronic NOEC <0.01 mg/L or CMR** or endocrine disrupting effects.

Not applicable.

* For the purpose of marine environmental risk assessment, half-life data in freshwater and freshwater sediment can be overruled by data obtained under marine conditions.

** Carcinogenic, Mutagenic or Reprotoxic (Ref. 3, R.11)

With regard to the compounds that have a PEC/PNEC ratio <1, and at the same time are PBTs and/or vPvBs, these would not be labelled as posing an insignificant or low risk, but rather refer to the hazard information in the detailed background information in accordance with Table 10.

The calculated PEC/PNEC ratio is ≤ 1. Hence, risk assessment procedures would indicate that “Compound A” would have insignificant/low* long-term risk to the environment. However, the half-life in the environment** is >xx days, the BCF is >2000 and the chronic toxicity is <0.01 mg/L (NOEC). “Compound A” should therefore be regarded as a PBT substance, according to the ECHA Guidance criteria, and as such the current PEC/PNEC ratio may underestimate the potential for long-term risks to aquatic organisms.

The calculated PEC/PNEC ratio is ≤ 1. Hence, risk assessment procedures would indicate that “Compound A” would have insignificant/low* long-term risk to the environment. However, the half-life in the environment** is >xx days and the BCF is >5000. “Compound A” should therefore be regarded as a vPvB substance, according to the ECHA Guidance criteria, and as such the current PEC/PNEC ratio may underestimate the potential for long-term risks to aquatic organisms.

Use of the medicine has been considered to result in moderate/high* environmental risk. In addition, the half-life in the environment** is >xx days, the BCF is >2000 and the chronic toxicity is <0.01 mg/L (NOEC). “Compound A” should therefore be regarded as a PBT substance according to the ECHA Guidance criteria.

Use of the medicine has been considered to result in moderate/high* environmental risk. In addition, the half-life in the environment** is >xx days and the BCF is >5000. “Compound A” should therefore be regarded as a vPvB substance according to the ECHA Guidance criteria.

3. Quality assurance process

Development of this guideline has been overseen by a multi stakeholder group including representatives from the research-based pharmaceutical industry, LIF, the Stockholm County Council, the Swedish Association of Local Authorities and Regions, the pharmacy monopoly chain Apoteket AB (today the Swedish Pharmacy Association represents the pharmacies), and the Swedish Medical Products Agency.

To ensure consistent application of the guideline, an independent reviewer, IVL, the Swedish Environmental Research Institute, has been appointed to review the information submitted by companies (Figure 2). The reviewer will check the data submitted and that the guideline has been applied correctly, making recommendations for amendments where appropriate. On occasions the reviewer may request further information from the company, via LIF, if required to support the proposed classification phrases. However, it is important to note that individual companies are ultimately responsible for the environmental summaries entered into the Fass database.

FIGURE 2

Figure 2. Partners in the quality assurance process of environmental classification at www.fass.se.

4. References

Committee for Medicinal Products for Human Use (CHMP); Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. 1 June 2006, Ref EMEA/CPMP/SWP/4447/00.

5. Appendix 1 - Template for environmental information at www.fass.se

Environmental risk: Use of *name of the substance* has been considered to result in insignificant environmental risk.

Degradation: *Name of the substance* is slowly degraded in the environment.

Bioaccumulation: *Name of the substance* has low potential for bioaccumulation.

Detailed background information

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*109*(100-R))/(365*P*V*D*100) = 1.5*10-6*A(100-R)

PEC = xx μg/L

Where:

A = xx kg (total sold amount API in Sweden year 20xx, data from LIF). Reduction of A may be justified based on metabolism data.

R = X % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available. (If R is not 0 this should be justified under the degradation section)

Substance X passes the ready degradation test but is not inherently degradable. The phrase “*Name of the substance* is slowly degraded in the environment” is thus chosen.

*If the degradation test is not standardised please specify the test with the following additional data if available; source & concentration of inoculum, information on pre-exposure, temperature, test substance concentration, DO, pH, analyte (e.g. parent compound or CO2), number of time points, number of replicates & test geometry.

Bioaccumulation

Bioconcentration factor (BCF):

Test result (guideline eg OECD 305). (Reference)

Partitioning coefficient:

e.g. Log Dow = xx at pH 7 (guideline eg OECD 107). (Reference)

Justification of chosen bioaccumulation phrase:

Since BCF < 500, the substance has low potential for bioaccumulation.

or;

Since log Dow < 4 at pH 7, the substance has low potential for bioaccumulation.

Excretion (metabolism)

Substance X is excreted to xx% as parent compound and to xx% as metabolites. The pharmacological activity of the metabolites is not known. (Reference)

A reduction of A (total sold amount API in Sweden 20xx) in the PEC calculation based on metabolism should be justified here.

PBT/vPvB assessment

If Substance X fulfils the criteria for PBT and/or vBvP this should be flagged and the following phrase should be added: According to the established EU criteria, the compound should be regarded as a PBT/vPvB substance.

“A study can be well conducted and fully reported but the test endpoint may have little ecological significance. Studies used for EQS development should be those where the test endpoint can be related to ecologically significant hazards. For practical purposes, this means effects that can be linked to population sustainability and particularly:

survivorship of adults

time taken to develop (particularly to reach reproductive age)

reproductive output

Most standard test methods include one or more of these endpoints. However, the assessor may be faced with data from studies describing endpoints that do not include direct measurements of survival, development or reproduction e.g. behavioural effects, anatomical differences between control and treatment groups, effects at the tissue or sub-cellular level, such as changes in enzyme induction or gene expression. Generally these are unsuitable as the basis for EQS derivation. However, anatomical changes to gonad development that would prevent successful reproduction, or changes in behaviour if the effect described would impair competitive fitness may be relevant.”

For more guidance on criteria that are suitable to evaluate non-standardised tests, please see Küster et al. (2009) (Ref. II).